Iron levels have been found by several investigators to be significantly increased in the substantia nigra of Parkinsonian patients vs. age-matched controls. This along with iron's ability to catalyze conversion of hydrogen peroxide produced as a by-product of dopamine metabolism to deleterious hydroxyl radical has lead to the hypothesis that iron may be involved in disease pathology via increased production of oxidative stress. Epidemiological studies performed to date have found no correlation between increased incidence of Parkinson's disease and either high dietary iron intake in the adult or prolonged occupational exposure to iron alone. However the role of early iron exposure on susceptibility to the disease has not yet been fully explored. What effects do neonatal iron exposure, genetic variations in iron metabolic factors, and increasing age have on susceptibility of dopaminergic nigral neurons to degeneration associated with Parkinson's disease? We plan to explore these questions by examining the effects of increased dietary iron on generation of oxidative stress and dopaminergic nigral cell degeneration in both the absence and presence of the Parkinsonian-inducing agent 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) in C57BI mice of various ages. In addition the combined effects of increased neonatal dietary iron and aging on susceptibility to MPTP will be examined in transgenic mouse lines recently constructed in our laboratory in which expression of the iron-binding protein ferritin has been up-regulated in dopaminergic nigral neurons. This will allow us to explore how combined variations in both dietary and endogenous metabolic factors in association with increasing age may predispose individuals for this disease and perhaps give us clues as to possible preventative interventions.